Techniques of treating neurodegenerative disorders by brain infusion

ABSTRACT

Techniques for infusing drugs into the brain to treat neurodegenerative disorders by system of an implantable pump and catheter. The drugs are capable of altering the level of excitation of neruons in the brain. A sensor is used to detect an attribute of the nervous system which reflects the hyperexcitation of the nerve cells projecting onto the degenerating nerve cells. A microprocessor algorithm analyzes the output from the sensor in order to regulate the amount of drug delivered to the brain.

This is a divisional of application Ser. No. 08/640,358, filed Apr. 30,1996, now U.S. Pat. No. 5,735,814 for which priority is claimed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to brain infusion techniques, and moreparticularly relates-to such techniques for treating neurodegenerativedisorders.

2. Description of Related Art

Neuroscientists have recognized and continue to explore excitotoxicity,a phenomenon referring to excessive excitation of nerve cells leading todegeneration of the nervous system. This phenomena has been used toexplain cell loss after stroke or some other hypoxic event. The researchhas focused on nerve cells that have glutamate neurotransmitterreceptors especially susceptible to the sustained insult.Hyperexcitation of these nerve cells is fundamental to the mechanism(Rothman, S. M., Olney, J. W. (1987) Trends Neurosci. 10, 299-302).Researchers have also used excitotoxicity to explain the observed cellloss in the CA1 region of the Horn of Ammon in the dentate gyrus ofhippocampus in patients and animal subjects that have suffered fromseizure activity. Seizures can be viewed as a form of abnormal overexcitation of the nerve cells in this region.

Typically, neuroscientists have focused on nerve cells that use thetransmitter substance glutamate to communicate with target nerve cells;however, other excitatory amino acids (EAA) are included. When nervecells are abnormally active, experiencing excessive action potentials,they are believed to release excessive amounts of glutamate or other EAAat their synaptic terminals. The presence of excessive amounts ofglutamate leads to toxic effects on the secondary nerve cells targetedby the hyperactive ones. These toxic effects are believed to be mediatedby an accumulation of calcium.

Benabid et al. (The Lancet, Vol 337:Feb. 16, 1991, pp 403-406) has shownthat stimulation of the Vim nucleus of the Thalamus will block tremor.In this instance, stimulation at frequencies around 100 to 185 pulsesper second accomplishes the same physiological response as a lesion ofthis region. Thus, it appears that stimulation inhibits the output ofthese cells. Benabid's research team has extended this work tostimulation of the subthalamus ("Vim and STN Stimulation in Parkinson'sdisease", Movement Disorders, Vol. 9, Supplement 1 (1994); "Effect onParkinsonian signs and symptoms of bilateral subthalamic nucleusstimulation", The Lancet, Vol 345, Jan. 14, 1995.

Parkinson's disease is the result of degeneration of the substantianigra pars compacta. The cells of subthalamus have been shown to useglutamate as the neurotransmitter effecting communication with theirtarget cells of the basal ganglia. The state of hyperexcitation thatexists in Parkinson's disease will cause an excessive release ofglutamate. This, in theory, will lead to further degeneration via themechanism described above.

Benabid has proposed a method of arresting degeneration of thesubstantia nigra by high frequency electrical pulsing of the subthalamicnucleus to block stimulation of the subthalamic nucleus, therebyinhibiting excessive release of glutamate at the terminal ends of theaxons projecting from the subthalamic nucleus to the substantia nigra.

Amotrophic Lateral Sclerosis (ALS), sometimes referred to as LouGerhig's disease, is a progressive neurodegenerative disease affectingthe voluntary motor system. The degeneration of the spinal cord andcortical motor neurons results in paralysis, respiratory depression anddeath. Glutamate neurons appear to be overactive in this disease stateand are suspected of causing the neurodegeneration (S. H. Apel,"Excitotoxic neuronal cell death in amyotrophic lateral sclerosis",TINS, Vol. 16, No. 1, 1993).

Huntington's disease is a degenerative disorder characterized bychoreathetosis which is at first slight. Usually, the choreathetosis isaccompanied by hypotonus. The motor dysfunction, associated withexcitatory transmitter neurotoxicity, may be accompanied by subtle formsof mental disorder that progress to a deterioration of cognitivefunction.

SUMMARY OF THE INVENTION

A preferred form of the invention can treat a neurodegenerativedisorder, such as Parkinson's disease Huntington's or AmyotrophicLateral Sclerosis (ALS), by means of an implantable pump and a catheterhaving a proximal end coupled to the pump and having a discharge portionfor infusing therapeutic dosages of the one or more drugs capable ofaltering the level of excitation of neurons of the brain. The catheteris implanted in the brain so that the discharge portion lies adjacent toa predetermined infusion site in the basal ganglia or thalamus of thebrain. Alternatively, the catheter may be implanted in a ventricle ofthe brain or subdurally so that the discharge portion lies within thecerebral spinal fluid (CSF). The pump is operated to discharge apredetermined dosage of the one or more drugs through the dischargeportion of the catheter into the infusion site. By using the foregoingmethod, the neurodegeneration that occurs in diseases, such asParkinson's disease, Huntington's disease and Amyotrophic LateralSclerosis, can be alleviated or prevented.

According to one embodiment of the invention, one or more drugs candecrease excitement of the subthalamus or increase inhibition of thesubthalamus. According to another embodiment of the invention, the oneor more drugs can increase excitement of the thalamus or decreaseinhibition of the thalamus.

Another form of the invention uses a sensor in combination with theimplantable pump and. catheter to administer one or more drugs capableof altering the level of excitation of nerurons of the brain to treat aneurodegenerative disorder. In this form of the invention, the sensorgenerates a signal relating to an attribute of the nervous system whichindicates the hyperexcitation of the degenerating neurons or the neuronsrelated to the degenerating neurons. Control means responsive to thesensor signal regulate the therapeutic dosage. For example, the dosagecan be increased in response to an increase in the hyperexcitation ofthe neurons and is decreased in response to a decrease in thehyperexcitation of the neurons

By using the foregoing techniques, neurodegeneration can be controlledto a degree unattainable by prior art methods or apparatus.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages and features of the invention will becomeapparent upon reading the following detailed description and referringto the accompanying drawings in which like numbers refer to like partsthroughout and in which:

FIG. 1 is a diagrammatic illustration of a portion of the nervous systemof the human body in which a preferred form of hyperexcitation sensor,pump and catheter have been implanted;

FIG. 2 is a schematic block diagram of a sensor and analog to digitalconverter circuit used in the preferred embodiment of the invention; and

FIG. 3 is a flow chart illustrating a preferred form of a microprocessorprogram for utilizing the sensor to control the dosage of drugadministered to the brain.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, a system or device 10 made in accordance with thepreferred embodiment may be implanted below the skin of a patient. Thedevice has a port 14 into which a hypodermic needle can be insertedthrough the skin to inject a quantity of a liquid agent, such as amedication or drug. The liquid agent is delivered from device 10 througha catheter port 20 into a catheter 22. Catheter 22 is positioned todeliver the agent to specific infusion sites in a brain (B). Device 10may take the form of the like-numbered device shown in U.S. Pat. No.4,692,147 (Duggan), assigned to Medtronic, Inc., Minneapolis, Minn.,which is incorporated by reference.

The distal end of catheter 22 terminates in a cylindrical hollow tube22A having a distal end 115 implanted into a portion of the basalganglia of the brain by conventional stereotactic surgical techniques.Additional details about end 115 may be obtained from pending U.S.application Ser. No. 08/430,960 entitled "Intraparenchymal InfusionCatheter System," filed Apr. 28, 1995 in the name of Dennis Elsberry etal. and assigned to the same assignee as the present application. Tube22A is surgically implanted through a hole in the skull 123 and catheter22 is implanted between the skull and the scalp 125 as shown in FIG. 1.Catheter 22 is joined to implanted device 10 in the manner shown. Device10 is implanted in a human body in a subcutaneous pocket located in thechest below the clavicle. Alternatively, device 10 may be implanted inthe abdomen.

In a second embodiment, distal end 115 of cylindrical hollow tube 22Amay be implanted in a ventricle. Alternatively, the distal tip may belocated in subdural area SD beneath the dura under the skull 123 butoutside the brain B.

Catheter 22 may be divided into twin tubes 22A and 22B (not shown) thatare implanted into the brain bilaterally. Alternatively, tube 22B (notshown) implanted on the other side of the brain may be supplied withdrugs from a separate catheter and pump.

A sensor 130 is implanted into a portion of a patient's central nervoussystem. As shown in FIG. 1, sensor 130 comprises a sensing lead 26having two sensing electrodes 28 and 30 located in the subthalamicregion, substantia nigra or other brain region whose electrical activityindicates the activity of the degenerating neurons, i.e., the neuronsexhibiting hyperexcitation. Alternatively, electrodes 28 and 30 could becarried by tube 22A. Electrodes 28 and 30 are connected to an analog todigital converter 140 (FIG. 2) by conductors 134 and 135 which arelocated within catheter 22. The potentials sensed by electrodes 28 and30 indicate the electrical activity in the subthalamic nucleus andconsequently the substantia nigra. Electrodes 28 and 30 transmit asignal related to the excitation of the portion of the brain exhibitinghyperexcitation. More specifically, electrodes 28 and 30 sense anattribute of the nervous system which indicates the hyperexcitation ofthe nerve cells projecting onto the degenerating nerve cells or thehyperexcitation of the degenerating nerve cells. Sensor 130 may take theform of a device capable of detecting nerve cell electrical activitythat is related to the hyperexcitation. Such a sensor may be locateddeep in the brain. For such detecting, sensor 130 may take the form ofan electrode inserted into one of the nuclei of the basal ganglia, thethalamus, the internal capsule or the cortex of the brain.Alternatively, such a sensor may be located outside the dura in the boneof the cranium. Signals that are received by the sensor may by amplifiedbefore transmission to circuitry contained within device 10.

Alternatively, sensor 130 may electronically transduce the concentrationof a transmitter substance infused into the brain or releasedendogenously. A paper describing such a sensor is entitled "MultichannelSemiconductor-based Electrodes for In Vivo Electrochemical andElectrophysiological Studies in Rat CNS", by van Horne et al., 120Neuroscience Letters 249-252 (Elsevier Scientific Publishers IrelandLtd. 1990).

Referring to FIG. 2, the output of sensor 130 is coupled by a cable 132comprising conductors 134 and 135 to the input of analog to digitalconverter 140. The output of the analog to digital converter isconnected to terminals EF2 BAR and EF3 BAR shown in FIG. 11A of U.S.Pat. No. 4,692,147 ("'147 Patent"). Before converter 140 is connected tothe terminals, the demodulator 101 currently shown in FIG. 11A would bedisconnected.

The present invention may be implemented by providing seven differentdrug dosages from 0 dosage to a 1.0 ml dosage with 0.1 ml incrementsbetween choices. The time interval between dosages can be selectedbetween one and twelve hours in seven choices. This is the same type ofdosage and interval described in connection with device 10 shown in the'147 Patent (column 5, beginning at line 63). The seven drug dosages andcorresponding time increments may be loaded into RAM 102a (FIG. 11B) ofthe '147 Patent. The appropriate drug dosage and interval is selected bya computer algorithm that reads the output of converter 140 and makesthe appropriate selection.

One exemplary computer algorithm is shown in FIG. 3. Microprocessor 100included within device 10 reads converter 140 in step 150, and storesone or more values in RAM 102a in step 152. One of seven dosages isselected in step 154, and an appropriate time interval is selected instep 156. The selected dosage and interval of a drug is then deliveredthrough catheter 22 and tube 22A to the basal ganglia of the brain bythe pump of the type as described in the '147 Patent.

For some types of sensor, a microprocessor and analog to digitalconverter will not be necessary. The output from sensor 130 can befiltered by an appropriate electronic filter in order to provide acontrol signal for a pump of the type shown in the '147 Patent.

The type of drugs administered by device 10 into the brain depend on thespecific location at which distal end 115 of tube 22A is surgicallyimplanted. The appropriate drugs for use in connection with the portionof the basal ganglia or thalamus in which tube 22A terminates, togetherwith the effect of the drug on that portion of the brain for reducingthe hyperexcitation of the subthalamic nucleus for the purpose oftreating Parkinson's degeneration is provided in Table I:

                  TABLE I                                                         ______________________________________                                        EFFECT         PORTION OF BRAIN                                                                            DRUG                                             ______________________________________                                        INCREASE EXCITATION                                                                          VL THALAMUS   glutamate agonist                                DECREASE INHIBITION                                                                          VL THALAMUS   GABA antagonist                                  INCREASE INHIBITION                                                                          GPi/SNr       GABA agonist                                     DECREASE EXCITATION                                                                          GPi/SNr       Glutamate                                                                     antagonist                                       INCREASE INHIBITION                                                                          STN           GABA agonsit                                     DECREASE EXCITATION                                                                          STN           Glutamate                                                                     antagonist                                       INCREASE EXCITATION                                                                          GPe           glutamate agonist                                DECREASE INHIBITION                                                                          GPe           GABA antagonist                                  INCREASE DOPAMINE                                                                            NEOSTRIATUM   Dopamine agonist                                 ______________________________________                                    

In the foregoing Table I, VL Thalamus means ventrolateral thalamus; GPimeans internal segment of globus pallidus; SNr means substantia nigrapars reticulata, STN means subthalamic nucleus; and GPe means externalsegment of globus pallidus.

Alternative targets and infusion strategies are appropriate fortreatement of degenerative disorders that are hyperkinetic in nature.For treatment of amyotrophic lateral sclerosis appropriate drugs for usein connection with the portion of the spinal cord, cerebral motorcortex, basal ganglia, and thalamus in which tube 22A terminates,together with the effect of the drug on that portion of the nervoussystem for decreasing excitation of the thalamic pathway is provided inTable II.

                  TABLE II                                                        ______________________________________                                                       TARGET                                                         EFFECT         STRUCTURE    DRUG                                              ______________________________________                                        DECREASE EXCITATION                                                                          MOTOR CORTEX GLUTAMATE                                                                     ANTAGONIST                                        DECREASE EXCITATION                                                                          SPINAL CORD  PKC INHIBITOR                                                    ANTERIOR HORN                                                  DECREASE EXCITATION                                                                          SPINAL CORD  GLUTAMATE                                                        ANTERIOR HORN                                                                              ANTAGONIST                                        DECREASE EXCITATION                                                                          VL THALAMUS  GLUTAMATE                                                                     ANTAGONIST                                        INCREASE INHIBITION                                                                          VL THALAMUS  GABA AGONIST                                      DECREASE INHIBITION                                                                          GPi/SNr      GABA                                                                          ANTAGONIST                                        INCREASE EXCITATION                                                                          GPi/SNr      GLUTAMATE                                                                     AGONIST                                           DECREASE INHIBITION                                                                          STN          GABA                                                                          ANTAGONIST                                        INCREASE EXCITATION                                                                          STN          GLUTAMATE                                                                     AGONIST                                           DECREASE EXCITATION                                                                          GPe          GLUTAMATE                                                                     ANTAGONIST                                        INCREASE INHIBITION                                                                          GPe          GABA AGONIST                                      DECREASE DOPAMINE                                                                            NEOSTRIATUM  DOPAMINE                                                                      ANTAGONIST                                        ______________________________________                                    

Stereotaxic coordinates based on a normal brain for the portions of thebrain described in

Tables I and II are identified in the following Table III:

                  TABLE III                                                       ______________________________________                                                  MEDIAL-     DORSAL-    ANTERIOR-                                              LATERAL     VENTRAL    POSTERIOR                                    BRAIN REGION                                                                            DIMENSION   DIMENSION  DIMENSION                                    ______________________________________                                        VL Thalamus                                                                             0.7 to 1.8  1.5 to -0.2                                                                              0.0 to -1.0                                  Gpi       0.5 to 2.0  0.5 to -0.7                                                                              0.7 to 2.0                                   SNr       0.5 to 1.5  -0.6 to -1.5                                                                             0.7 to -0.7                                  STN       0.5 to 2.0  0.0 to -1.0                                                                              0.6 to -1.0                                  GPe       1.6 to 2.7  1.0 to -1.0                                                                              2.0 to -1.0                                  Striatum:                                                                     Caudate   0.5 to 2.0  1.5 to 3.0 1.5 to 3.0                                   Putamen   1.2 to 3.3  1.5 to -1.0                                                                              2.5 to -1.2                                  ______________________________________                                    

In the foregoing table: the medial-lateral dimensions are relative tomidline of the brain; the anterior-posterior dimensions are relative tothe midpoint between the anterior commissure and posterior commissurewith negative indicating the posterior direction; the dorsal-ventraldimensions are relative to a line connecting the midpoints of theanterior and posterior commissures with negative being ventral to saidline; all dimension are in centimeters.

Preferred ranges of dosages and specific drugs for the brain infusionsites identified in Tables I and II are provided in the following TableIV:

                  TABLE IV                                                        ______________________________________                                        DRUG CLASS  SPECIFIC DRUG   DOSING RANGE                                      ______________________________________                                        Glutamate Agonist                                                                         D-Cycloserine   1-10 muM                                                      L-AP4           1-10 muM                                                      Carboxyphenylglycine                                                                          10-500 muM                                                    L-glutamic acid 1-100 muM                                                     cis-Piperidine-2,3-                                                                           1-10 muM                                                      dicarboxylic acid                                                             (+/-)-trans-ACPD                                                                              1-10 muM                                                      L-AP4           1-10 muM                                          Glutamate Antagonists                                                                     MK801(dizocilpine)                                                                            1-20 muM                                                      ketamine Hcl    5-50 muM                                                      AP-3            1-10muM                                                       Dextromethorphan                                                                              1-100 muM                                                     MCPD            0.02-10 muM                                                   dextrorphan tartrate                                                                          1-100 muM                                                     CNQX            1-100 muM                                         GABA Agonists                                                                             baclofen        0.1-10 muM                                                    muscinol HBr    100-500 muM                                       GABA Antagonists                                                                          Gabazine        1-50 muM                                                      Saclofen        0.5-25 muM                                                    Bicuulline      1-100 muM                                                     picrotoxin      10-100 muM                                        Dopamine Antagonist                                                                       (+) apomorphine Hcl                                                                           5-20 muM                                                      spiperone Hcl   0.1-10 muM                                                    haloperidol     10-100 muM                                                    (-) Sulpiride   0.05-1 muM                                        Dopamine Agonist                                                                          methanesulfonate                                                                              1-10 muM                                                      (-) apomorphine pergolide                                                                     10-30 muM                                         Anesthetic  Lidocaine hydrochloride                                                                       5-20 muM                                          ______________________________________                                    

In the preceding table, muM means micromolar.

Alternatively, these agents might be infused into the lateral ventricleor third ventricle of the brain or just beneath the dura above thecortex or in the intrathecal space. In this instance the drug woulddiffuse to the appropriate site of action.

Microprocessor 100 within device 10 can be programmed so that acontrolled amount of drug can be delivered to the specific brain sitesdescribed in Tables I and II. Alternatively, sensor 130 can be used witha closed loop feedback system in order to automatically determine thelevel of drug delivery necessary to alleviate the hyperexcitation asdescribed in connection with FIG. 3.

By using the foregoing techniques, neurodegenertive disorders can becontrolled in a manner previously unattainable.

Those skilled in that art will recognize that the preferred embodimentsmay be altered or amended without departing from the true spirit andscope of the invention, as defined in the accompanying claims.

We claim:
 1. A system for treating a neurodegenerative disorderresulting in degenerating neurons forming part of a central nervoussystem comprising in combination:an implantable pump; a catheter havinga proximal end coupled to said pump and a discharge portion for infusinginto a predetermined infusion site in said central nervous system atherapeutic dosage of at least one drugs capable of altering the levelof excitation of neurons in said brain related to a degeneratingneurons; a sensor for generating a signal related to an attribute ofsaid nervous system which indicates the hyperexcitation of saiddegenerating neurons or of neurons related to said degenerating neurons;and control means responsive to said sensor signal for regulating saidtherapeutic dosage.
 2. A system, as claimed in claim 1, wherein saidsensor comprises means for detecting changes in electromagnetic wavesgenerated by muscle or nerve tissue.
 3. A system, as claimed in claim 1,wherein said sensor comprises means for detecting the extent of thehyperexcitation of the glutamatergic neurons of said brain.
 4. A system,as claimed in claim 1, wherein said control means comprises amicroprocessor.
 5. A system, as claimed in claim 1, wherein said controlmeans comprises an electrical filter.
 6. A system, as claimed in claim1, wherein said control means comprises means for increasing saidtherapeutic dosage in response to an increase in said hyperexcitationand for decreasing said therapeutic dosage in respone to a decrease insaid hyperexcitation.
 7. A system, as claimed in claim 1, wherein saidpredetermined infusion site is selected from the group consisting of thebrain, the cerebral ventricle, the subdural space or the intrathecalspace.